Biology subjects

Ishiyama, S.

Publications and source records attributed to Ishiyama, S..

6 recordsLinked to original sources

bioRxiv2025

Age-Dependent, Odorant-Specific Changes in Olfactory Sensitivity in an Alzheimer's Disease Mouse Model

BackgroundOlfactory impairment often precedes cognitive decline in Alzheimers disease (AD). Recent studies suggest odor specificity in olfactory deficits during early AD stages, making olfactory tests a promising tool for early diagnosis. However, the mechanisms underlying olfactory impairment remain unclear, complicating the identification of optimal odorants for diagnostic purposes. ObjectiveIn this study, we assessed olfactory sensitivity in a knock-in mouse model of Alzheimers disease (AppNL-G-F mice) that recapitulates key features of human AD pathology. MethodsTo evaluate odor detection thresholds, we employed an olfactory assay that leverages innate behavior without requiring associative learning. Six odorants representing distinct functional groups were tested in wild-type (WT) and AppNL-G-F mice at 2 and 4 months of age. ResultsAppNL-G-F mice exhibited odorant-specific hyposmia at 4 months of age, coinciding with amyloid deposition in cortical and subcortical regions but preceding measurable cognitive deficits. Unexpectedly, at an earlier stage (2 months), these mice showed odorant-specific hyperosmia to ester odorants, which transitioned to hyposmia by 4 months, indicating dynamic, age-dependent alterations in olfactory sensitivity as AD pathology progresses. ConclusionsOur findings demonstrate that odorant-specific olfactory testing could serve as a promising diagnostic tool for early-stage AD, providing insights into the mechanisms underlying olfactory dysfunction in neurodegenerative diseases.

pathology↗

bioRxiv2024

Structural basis for bispecific antibody design: arrangement of domain linkage produces activity enhancement

A bispecific antibody (BsAb) is a protein genetically engineered from two different antibodies, allowing simultaneous binding to two kinds of antigen to bring them into close proximity. BsAbs have been developed as anti-cancer drugs that accumulate lymphocytes onto cancer cells by bridging antigens present on each. Ex3 is a bispecific diabody composed of the two fused variable regions (Fvs) of an anti-epidermal growth factor receptor (EGFR) antibody and an anti-CD3 antibody with potent cancer cytotoxic activity. In Ex3, the LH-type, in which the variable regions of the light chain (VLs) are located at the N-terminus of those of the heavy chain (VHs), exerted 1000-fold greater anticancer activity than the HL-type, in which the VHs are located at the N-terminus of the VLs. This effect (termed activity enhancement), in which the activity is greatly enhanced by domain rearrangement, has been reported not only for Ex3 but also for several other BsAbs. However, the molecular details of this activity enhancement have yet to be elucidated. In this study, we determined the cryo-EM structures of Ex3 LH- and HL-types in complex with CD3 and EGFR. Structural comparison of the LH- and HL-types showed that rearrangement of the domain linkage produces drastic structural differences in the overall shape of these complexes, and dynamics attributed to the flexibility between the two Fvs. These findings provide valuable insights into the molecular mechanism for the activity enhancement of BsAbs. This study will be a stepping stone towards establishing a design foundation for BsAb development.

biochemistry↗

bioRxiv2024

Rat Anterior Insula Symmetrically Represents Tickling-Induced Playful Emotions

Social play, an integral aspect of animal behavior, is inherently associated with positive emotions, yet the neuronal underpinnings of these playful states remain inadequately explored. We examined the anterior insulas involvement in processing tickle-induced playful emotions in rats. Our findings revealed diverse patterns of insular activity during tickling, with 20% of the recorded units displaying strong activation, and another 20% exhibiting inhibition. These units responded similarly to other playful contexts, such as gentle touch and hand chase, but not to neutral locomotion. Tickle-activated units demonstrated a positive correlation of firing rates with appetitive vocalization rates, whereas tickle-inhibited units showed a negative correlation. Distinct spike waveforms were associated with the tickle response patterns, suggesting potential cell-type dependencies. However, pharmacological manipulation of the global anterior insula did not yield observable effects on play behavior in rats. Anterograde tracing revealed extensive insular projections to areas including the amygdala and nucleus accumbens. Taken together, our findings suggest that the anterior insula symmetrically represents tickle-induced playful emotional states.

neuroscience↗

bioRxiv2024

Comparative Analysis of Tickling and Conspecific Play in Tame Mice and Golden Hamsters

Social play behavior is a fundamental aspect of animal interaction, shaping social bonds and enhancing cognitive capacity. While studies on human-animal play interactions have primarily focused on a few selected species, research on rodents beyond rats remains scarce. We, therefore, addressed the dynamics of social play in tame mice, selectively bred to approach human hands, and golden hamsters, comparing their responses during interactions with humans and conspecifics. Tame mice exhibited heightened playfulness with humans, marked by increased vocalizations and chasing behavior, in addition to increased interactions with tame conspecifics compared to unselected control mice. Hamsters demonstrated a stronger inclination towards conspecific interactions. Notably, vocalization patterns varied between heterospecific and conspecific engagement in both species, suggesting context-dependent communication. These findings offer insights into the evolutionary basis influencing social play across species with differing social structures. Understanding these mechanisms enriches our comprehension of the diverse pathways through which animals form social bonds.

animal behavior and cognition↗

bioRxiv2023

ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1

Nearly 30% of Pancreatic ductal adenocarcinoma (PDAC)s exhibit a marked overexpression of Monocarboxylate Transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study we present an alternative approach using 3-Bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), that is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule. One Sentence SummaryME3BP-7 is a novel formulation of 3BP that resists serum degradation and rapidly kills pancreatic cancer cells expressing high levels of MCT1 with tolerable toxicity in mice.

cancer biology↗

bioRxiv2021

Tickle contagion in the somatosensory cortex

The cellular mechanisms of emotional contagion are unknown. We investigated tickle contagion and the underlying neuronal representations in rats. We recorded trunk somatosensory cortex activity of observer rats while they received tickling, audio-visual playback of tickling footage, and while they witnessed tickling of demonstrator rats. Observers vocalized, and showed "Freudensprunge" ("joy jumps") during witnessing live tickling, while they showed little behavioral responses to playbacks. A fraction of trunk somatosensory neurons responded to both direct and witnessed tickling in action-specific manner. The correlation between direct and witnessed tickling responses increased towards deeper cortical layers. Tickle-mirror neurons but not non-mirror neurons discharged prior to and during vocalizations and hence might drive contagious laughter. We conclude that trunk somatosensory cortex represents mirrored ticklishness.

neuroscience↗